US5219728A - Soluble forms of low affinity fc gamma receptors, process for their identification and dosage, a corresponding dosage kit, and applications - Google Patents

Soluble forms of low affinity fc gamma receptors, process for their identification and dosage, a corresponding dosage kit, and applications Download PDF

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US5219728A
US5219728A US07/353,676 US35367689A US5219728A US 5219728 A US5219728 A US 5219728A US 35367689 A US35367689 A US 35367689A US 5219728 A US5219728 A US 5219728A
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antibody
receptor
daltons
fraction
monoclonal
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David Khayat
Jay Unkeless
Claude Jacquillat
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Universite Pierre et Marie Curie Paris 6
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Assigned to UNIVERSITE PIERRE ET MARIE CURIE, A CORP. OF FRANCE reassignment UNIVERSITE PIERRE ET MARIE CURIE, A CORP. OF FRANCE ASSIGNMENT OF ASSIGNORS INTEREST. Assignors: JACQUILLAT, CLAUDE, KHAYAT, DAVID, UNKELESS, JAY
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    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/68—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving proteins, peptides or amino acids
    • G01N33/6854—Immunoglobulins
    • G01N33/6857—Antibody fragments

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  • the present invention relates to soluble forms of low affinity receptors for the Fc fragment of IgG molecules; the present invention also relates to a method for the identification and assay of soluble forms of low affinity Fc gamma receptors, especially human soluble Fc receptors; it also relates to a kit of the reagents necessary for carrying out this method; it relates finally to the applications of this method for the diagnosis of pathological conditions in which the above-mentioned receptors are involved, such as infectious diseases, autoimmune diseases, transplant rejections, human complex diseases, cancers, myelomas and acquired immune deficiency syndrome (AIDS), for the therapeutic monitoring of the course of these conditions, as well as for the study of human polymorphisms.
  • infectious diseases infectious diseases, autoimmune diseases, transplant rejections, human complex diseases, cancers, myelomas and acquired immune deficiency syndrome (AIDS)
  • AIDS acquired immune deficiency syndrome
  • FcR Fc fragment of antibodies
  • these IBF molecules are capable, when they are in contact with B lymphocytes in culture, or even myeloma cells in vitro, of completely inhibiting the activation of these cells and, as a result, the secretion of immunoglobulins by these B or myeloma cells.
  • the molecules in question are hence secreted by cells belonging to the immune system under artificial conditions of in vitro culture, but are nevertheless endowed with a functional capacity to bind antibodies and to bring about a substantial suppression of the activation of the B lymphocyte system (lymphokine).
  • FcR mouse IgG immunoglobulins
  • this lymphokine is secreted at a level which increases with age (level zero at birth, appearing at around the fifth day in newborn mice and becoming systematically detectable at around the seventh day), that this level increases in proportion to the presence of infections or, more generally, that the immune system is stimulated (mice kept in a microbe-free environment having strictly zero levels throughout their life), this level being, moreover, determined in a relative manner by genetic factors within a population of homozygotic mice.
  • receptors are present in biological fluids (in particular serum) in polymerized form, as could be observed by molecular weight measurements which, for example, yielded a value above approximately 700,000 for the glycoprotein which has been shown to have a molecular weight in the monomer state of 72,000 to 76,000.
  • the subject of the present invention is a low affinity, soluble Fc ⁇ R type III receptor (or CD16), consisting of a glycoprotein of molecular mass 72,000-76,000 daltons which is recognized in ELISA and Western Blotting by the monoclonal antibody anti-Leu 11b.
  • the subject of the invention is also a low affinity, soluble Fc ⁇ R type III receptor (or CD16), which consists of the product obtained by affinity chromatography, on a column coupled to 3G8 antibodies or to lectins (for example Lens Culinaris Agglutinin (LCA), wheatgerm agglutinin or concanavalin) or to anti-FcR receptor polyclonal antibodies, of a biological fluid of human origin, followed by gel filtration, the spectrum of the said product, in acrylamide gel electrophoresis under reducing conditions, containing a major band corresponding to a molecular mass of between 72,000 and 76,000 daltons and a plurality of minor bands, of which the main ones correspond to molecular masses, respectively, of:
  • the invention also relates to an Fc ⁇ R type III receptor essentially comprising the fraction of molecular mass 33,000-37,000 daltons, as appears in acrylamide gel electrophoresis in the presence of a reducing agent and a detergent agent such as sodium dodecyl sulfate (SDS).
  • a reducing agent such as sodium dodecyl sulfate (SDS).
  • SDS sodium dodecyl sulfate
  • the biological fluids to which the present invention relates are, inter alia, serum and plasma fluids, cephalo-rachidian fluids, urines and ascitic fluids.
  • a feature of all these receptors which may be mentioned is that, in the Dot Blot technique, they recognize a rabbit anti-FcR receptor polyclonal antibody.
  • the invention finally relates to each of the fractions of the Fc ⁇ R type III receptor, as are defined above, as well as to all possible combinations of these fractions.
  • the present invention also relates to a method for the identification, detection or assay of these lymphokines having the capacity to bind to the Fc fragments of immunoglobulin, in particular the human serum soluble Fc receptor.
  • the method according to the present invention for the identification or assay of soluble forms of the low affinity Fc ⁇ R type III receptor (or CD16) consists in:
  • a first antibody which is a monoclonal or polyclonal antibody or alternatively a fraction of a monoclonal or polyclonal antibody (for example a Fab fragment), directed against a conformational epitope of the Fc ⁇ receptor to be identified or assayed;
  • a second antibody which is a monoclonal or polyclonal antibody, or alternatively a fraction of a monoclonal or polyclonal antibody (for example a Fab fragment), and which is an anti-Fc receptor recognizing the same category of Fc receptors as the first antibody, but by a completely different epitope;
  • the monoclonal antibody 3G8 is used, in particular, as the first antibody.
  • a mouse IgM consisting of the monoclonal antibody anti-Leu 11b is used, in particular, as the second antibody.
  • a polyclonal antibody, namely a goat anti-mouse IgM antibody is used as the third antibody.
  • a third antibody labeled with an enzyme is employed and, in the stage (i), a colorimetric substrate for the said enzyme is added and, after the colorimetric reaction has been stopped, for example by adding aqueous sulfuric acid solution, the colorimetric change is read, from which the quantity of Fc receptor sought is deduced.
  • the colorimetric change is proportional to the quantity of the third antibody and, as a result, proportional to the quantity of second antibody, and hence of Fc receptor initially present in the sample.
  • the enzyme is peroxidase, in particular horseradish peroxidase
  • the colorimetric substrate for peroxidase is ortho-phenylenediamine, in the presence of hydrogen peroxide, the colorimetric reading being performed at 492 nm.
  • the incubation of the stage (a), for the binding of the first antibody to the solid phase is performed, for example, at a temperature of the order of 4° C., for a period of time ranging from 8 to 12 hours.
  • FIG. 7 of the attached drawing explains the assay according to the invention.
  • the lymphokine sought which is assayed specifically by this method, contains a first site of capture by the first antibody (3G8), and a 10 second site of detection by the sequence ⁇ Leu 11b-goat anti-mouse IgM antibody and peroxidase.
  • the subject of the present invention is also the kit of the reagents necessary for carrying out this method, this kit comprising:
  • a solid support in particular a microtitration plate, provided with a first antibody which is a monoclonal or polyclonal antibody, or alternatively a fraction of a monoclonal or polyclonal antibody, and which is directed against a conformational epitope of the Fc ⁇ receptor to be assayed;
  • a second antibody which is a monoclonal or polyclonal antibody, or alternatively a fraction of a monoclonal or polyclonal antibody, and which is an anti-Fc receptor recognizing the same category of Fc receptors as the first antibody, but by a completely different epitope;
  • a third antibody which is an antibody capable of specifically recognizing the second antibody
  • xenogenic sera fetal calf, horse, goat
  • a positive known serum is used, and, in order to be able to quantify the method, an extract of human polymorphonuclear leukocytes are used.
  • These polymorphonuclear leukocytes are purified according to classical purification techniques, are counted and are then lysed with a mild detergent which does not destroy the conformational structures of the polymorphonuclear cell receptors, which would no longer be able to be recognized subsequently during the test with the 3G8 antibody, and, knowing the number of Fc receptors per polymorphonuclear cell, the number of polymorphonuclear cells at the start and the different dilutions at which these polymorphonuclear cells are tested, it is possible, by a simple relationship, to determine the correspondence between the soluble Fc receptors in the sera tested and a theoretical number of Fc receptors of polymorphonuclear cells detected in the cell lysate.
  • the applications of this method are essentially diagnostic applications and applications for monitoring the therapeutic use of these lymphokines.
  • the latter are, in effect, substances, the variations of which are linked to the fine activation of the B lymphocyte system and/or tho macrophage system and whose variation in level enables the state of stimulation of this system to be determined. This is of major importance in infectious diseases, autoimmune diseases, transplant rejections, cancers and myelomas, and acquired immune deficiency syndrome (AIDS).
  • AIDS acquired immune deficiency syndrome
  • lymphokine human Fc receptor
  • such a lymphokine is capable, like its in vitro homolog, of specifically inhibiting the secretion of an immunoglobulin class and hence of halting an effector mechanism in some pathological conditions, such as the abovementioned diseases, without thereby, as a result of its specificity--in effect, a receptor for IgG will bring about the inhibition of only IgG secretion--bringing about an inhibition of the secretion of the other immunoglobulin classes, hence enabling a resultant immunosuppression of the patient to be avoided.
  • this lymphokine may prevent the relationship between these immune complexes and the cells of the reticuloendothelial system which would normally have phagocytosed these antigens (platelets in the case of idiopathic thrombocytopenic purpura), leading to the pathogenic effect (thrombocytopenia in the chosen example).
  • the invention also relates to a medicinal product containing an Fc ⁇ R type III receptor or at least one fraction which is a constituent thereof, as are defined above.
  • microtitration plates used are 96-well U-bottomed poly(vinyl) chloride plates (manufactured by Societe "Dynatech”).
  • the monoclonal antibody 3G8 is introduced, on the basis of 3 ⁇ g per well, in 100 ⁇ l of carbonate buffer at pH 9.6. The incubation lasts 8 to 12 hours at a temperature of 4° C.
  • PBS Phosphate Buffered Saline
  • This washing is performed in the same manner as in the stage (2).
  • This washing is performed in the same manner as in the stage (2).
  • the abovementioned antibody (source: Jackson Immuno-Research Laboratories Inc.), diluted to 1/5,000 in PBS Tween producing in total 100 ⁇ l per well, is introduced. Incubation is performed for 1 hour at 22° C.
  • This washing is performed in the same manner as in the stage (2).
  • the colorimetric reaction is stopped by depositing 75 ⁇ l per well of 10% aqueous sulfuric acid solution, and the result is read at 492 nm in an ELISA reading apparatus.
  • a normal human serum (68 ml) is passed, in a first stage, through a column of Sepharose coupled to 3G8 monoclonal antibodies (2 mg of 3G8 antibody per ml of Sepharose; total column volume: 1 ml), at room temperature.
  • This column is then washed using 150 ml of a 0.1% strength solution of "Tween 20" in phosphate buffered saline solution, and the material adsorbed is then eluted using 1/2M acetic acid solution, the fragments having a volume of 0.5 ml. These fractions are immediately neutralized using 3M sodium bicarbonate solution.
  • the serum, before and after affinity chromatography, as well as the elution fractions, are tested for their content of soluble low affinity type III Fc receptor.
  • the fractions which show immunological activity are then combined, and 0.2 ml of this pool of fractions is subjected to gel filtration on a column of volume 25 ml of "Superose 6" (Pharmacia); this "Superose 6" column is equilibrated in 50 mM ammonium bicarbonate solution at pH 8.
  • the fractions having a volume of 0.5 ml are collected and tested using a direct ELISA assay method.
  • This ELISA method consists in testing the elution fractions without passing through the stage of capture using the monoclonal antibody 3G8.
  • fractions are affixed directly to a solid support of the 96-well PVC plate type, and are then, after washing, reacted with the monoclonal antibody anti-Leu 11b, followed, after 2 hours, by a second anti-mouse IgM antibody labeled with peroxidase.
  • FIG. 1 of the attached drawing shows the results of this second stage of the purification, hence corresponding to the gel filtration.
  • Two curves are seen in this figure.
  • the elution fraction numbers, as well as the time elapsed (expressed in minutes) are plotted as abscissae, and the optical density as seen on the reading of the wells in the direct ELISA method is plotted as ordinates.
  • the curve in the form of a continuous line corresponds to the elution chromatogram of this gel filtration, and gives only the quantity of proteins without giving their characteristics.
  • the second curve ( ⁇ -- ⁇ ) represents the immunoreactivity of each of the elution fractions, in terms of purified soluble Fc receptor. It is hence observed that the peak between the fractions 20 and 25 bears virtually the whole of the purified soluble Fc type III receptor type immunoreactivity.
  • the fractions 20 and 22 which are the richest in soluble Fc receptor type immunoreactivity since the optical density rises to around 2 units, were lyophilized, and they were subjected to acrylamide gel electrophoresis in the presence of SDS and a reducing agent. These fractions are shown in FIG. 2, and show the existence of a characteristic principal major band whose molecular weight is 72,000 to 76,000 daltons, but also bands of somewhat minor importance at around 66,000, 3,000, 43,000 and 35,000 daltons.
  • FIGS. 4 and 5 illustrate the results of adsorption experiments on columns of lectin.
  • the experiment was as follows: 500 microliters of normal human serum were deposited twice in succession, at room temperature, in an equivalent volume of agarose coupled to different lectins.
  • the lectin in question is that known as Lens Culinaris Agglutinin (or LCA).
  • LCA Lens Culinaris Agglutinin
  • the material adsorbed on this column was then eluted, that is to say detached; this is shown in FIG. 5; this was carried out by applying on the column a solution which enters into competition with the Fc receptor, namely a solution which contains the sugar specific for this lectin.
  • the elution solution is a 0.5M ⁇ -methyl mannoside solution.
  • FIG. 5 The immunoreactivity, as obtained using the classical sandwich ELISA technique, of the different elution fractions, which are numbered as abscissae, are shown in this figure, and the ordinates indicate the reactivity in ELISA in terms of optical density. It is seen that a classical elution curve, with a peak around the second and third fraction, is indeed obtained. This confirms once more that the Fc receptor according to the invention, as it circulates in the serum, is indeed a glycoprotein.
  • FIG. 6 illustrates the results of a so-called "Dot Blot” experiment.
  • the Dot Blot technique is fully known and referred to in the literature. According to this technique, a cellulose nitrate filter is brought into contact with a solution containing the antigens to be assayed. These antigens are bound to this cellulose nitrate paper by the application of a vacuum on the other side of this porous filter. As a result of the action of the vacuum, the antigen molecules become bound to the cellulose nitrate paper. This paper is then reacted with different antibodies and enables colorimetric reactions to be observed by means of the use of enzyme-labeled antibodies.
  • the sample is a cell extract, as also described above.
  • This cell extract is tested at four dilutions, from the left to the right of the figure, and shows a classical dilution curve with an immunoreactivity corresponding to the colorimetric reaction observed on the nitrocellulose filter which decreases progressively in proportion to the dilution.
  • the sample is a serum considered to be positive from the results of the sandwich ELISA technique according to the invention.
  • the test shows a decrease in the optical density obtained, proportional to the dilution of serum which also goes from the left to the right of the figure, hence showing that the reaction in question is equally as specific as that of the sandwich ELISA technique.
  • a serum was tested which was considered to be negative from the results of the sandwich ELISA technique, that is to say, when it is reacted in a first stage with capture by 3G8 on a PVC plate and in the second instance with the system comprising anti-Leu 11b antibody and peroxidase-labeled anti-mouse IgM polyclonal antibody, which usually gave a negative result, the presence was observed, in this negative serum, of material antigenically recognized as an Fc receptor.
  • immunoglobulins such as multiple myeloma or Kahler's disease.

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US07/353,676 1987-02-24 1988-02-23 Soluble forms of low affinity fc gamma receptors, process for their identification and dosage, a corresponding dosage kit, and applications Expired - Fee Related US5219728A (en)

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FR8702400A FR2611913B1 (fr) 1987-02-24 1987-02-24 Procede de dosage des recepteurs fc gamma solubles seriques, coffret de dosage correspondant et applications

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Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5767077A (en) * 1988-05-27 1998-06-16 Applied Research Systems Ars Holding N.V. Human Fc-γ receptor III
US5830652A (en) * 1994-08-30 1998-11-03 New York Society For The Ruptured And Crippled Maintaining The Hospital For Special Surgery Method for determining predisposition to severe forms of autoimmune disease by determining Fcy receptor allelic patterns
US5897861A (en) * 1989-06-29 1999-04-27 Medarex, Inc. Bispecific reagents for AIDS therapy
US5976831A (en) * 1988-05-27 1999-11-02 Applied Research Systems Ars Holding, N.V. Human FCγ receptor III
WO2003101485A1 (fr) * 2002-05-30 2003-12-11 Macrogenics, Inc. Proteines de liaison a cd16a et leur utilisation pour le traitement de troubles immunitaires
US20040265321A1 (en) * 2003-01-13 2004-12-30 Johnson Leslie S Soluble FcgammaR fusion protiens and methods of use thereof

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FR2655269B1 (fr) * 1989-12-01 1994-02-11 Curie Universite Pierre Marie Proteines empechant l'interaction entre un fragment fc d'une immunoglobuline et son recepteur et utilisation en therapeutique, notamment dans le traitement des affections liees aux virus hiv.
FR2702481B1 (fr) * 1993-03-09 1995-04-28 Roussel Uclaf Nouveaux récepteurs Fc-gamma III humains solubles, leur procédé de préparation, les compositions pharmaceutiques les contenant, leur application comme médicaments et leur application diagnostique.

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WO1986004421A1 (fr) * 1982-08-20 1986-07-31 Hygeia Sciences Limited Partnership Test immunologique enzymatique ayant comme chromogene une solution en deux parties de tetramethyle-benzidine
EP0119736A2 (fr) * 1983-02-16 1984-09-26 The Board Of Trustees Of The Leland Stanford Junior University Essais immunologiques "double-site" utilisant des anticorps monoclonaux de différente classes ou sous-classes et trousses de réactifs pour leur mise en oeuvre
EP0125893A2 (fr) * 1983-05-12 1984-11-21 Sumitomo Chemical Company, Limited Analyse quantitative d'antigènes par la méthode de "pont" enzyme-anticorps

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Cited By (16)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5767077A (en) * 1988-05-27 1998-06-16 Applied Research Systems Ars Holding N.V. Human Fc-γ receptor III
US5976831A (en) * 1988-05-27 1999-11-02 Applied Research Systems Ars Holding, N.V. Human FCγ receptor III
US6294347B1 (en) 1988-05-27 2001-09-25 Applied Research Systems Ars Holding N.V. Human FCγ receptor III
US5897861A (en) * 1989-06-29 1999-04-27 Medarex, Inc. Bispecific reagents for AIDS therapy
US5830652A (en) * 1994-08-30 1998-11-03 New York Society For The Ruptured And Crippled Maintaining The Hospital For Special Surgery Method for determining predisposition to severe forms of autoimmune disease by determining Fcy receptor allelic patterns
US20080050371A1 (en) * 2002-05-30 2008-02-28 Macrogenics, Inc. CD16A Binding Proteins and Use for the Treatment of Immune Disorders
US20070244303A1 (en) * 2002-05-30 2007-10-18 Macrogenics, Inc. CD16A Binding Proteins and Use for the Treatment of Immune Disorders
WO2003101485A1 (fr) * 2002-05-30 2003-12-11 Macrogenics, Inc. Proteines de liaison a cd16a et leur utilisation pour le traitement de troubles immunitaires
US7351803B2 (en) 2002-05-30 2008-04-01 Macrogenics, Inc. CD16A binding proteins and use for the treatment of immune disorders
AU2003232456B2 (en) * 2002-05-30 2009-06-04 Macrogenics, Inc. CD16A binding proteins and use for the treatment of immune disorders
US7618628B2 (en) 2002-05-30 2009-11-17 Macrogenics Inc. CD16A binding proteins and use for the treatment of immune disorders
US7838635B2 (en) 2002-05-30 2010-11-23 Macrogenics, Inc. CD16A binding proteins and use for the treatment of immune disorders
US20110152504A1 (en) * 2002-05-30 2011-06-23 Macrogenics, Inc. CD16A Binding Proteins and Use for the Treatment of Immune Disorders
US20040265321A1 (en) * 2003-01-13 2004-12-30 Johnson Leslie S Soluble FcgammaR fusion protiens and methods of use thereof
US7700100B2 (en) 2003-01-13 2010-04-20 Macrogenics, Inc. FcγRIIB fusion proteins and compositions thereof
US20100196372A1 (en) * 2003-01-13 2010-08-05 Macrogenics, Inc. FcgammaRIIB Fusion Proteins and Compositions Thereof

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FR2611913A1 (fr) 1988-09-09
FR2611913B1 (fr) 1994-04-15
EP0309496A1 (fr) 1989-04-05
WO1988006733A1 (fr) 1988-09-07

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